Organophosphate (OP) acetylcholinesterase inhibitors are used widely in agriculture as pesticides and also have been used in terrorist attacks against civilian populations. OPs are irreversible acetylcholinesterase inhibitors which can cause death due to overstimulation of both central and peripheral cholinergic systems. Overstimulation of muscarinic acetylcholine receptors (mAChR) in the central nervous system (CNS) can cause respiratory depression and convulsions. This research will use genetic, pharmacological, and molecular approaches to define underlying mechanisms of OP action in the CNS and to identify new pharmacological targets to prevent or ameliorate OP-induced actions in the CNS. OP-induced seizures progress through three neurochemical stages: an initial phase which can be blocked by muscarinic antagonists, followed by a transitional period where both cholinergic and noncholinergic pathways contribute to the seizures, and followed by mainly noncholinergic-mediated seizure activity. This proposal will use mouse strains deleted of specific mAChR genes to determine the subtype of receptor which mediates OP-induced convulsions. This proposal will also use pharmacological and genetic approaches to determine the roles of the noradrenergic and dopaminergic systems and their receptors in OP-induced seizures. Prevention and/or termination of OP- induced seizure activity is critical both for reduction of rapid lethality and pathological neurological changes. The cell damage after OP-induced seizures is followed by proliferation of neuronal precursor cells. This increased neurogenesis has been suggested to both contribute to and to limit the long-term damage caused by OP exposure. This proposal will also determine the mechanisms and contributions of convulsive and non- convulsive pathways to OP-induced cell death and neurogenesis. Environmental exposure to OP pesticides causes thousands of death world-wide. The dangers of the use of OP nerve agents in attacks on civilian populations was demonstrated by the sarin attacks in Japan in 1994 and 1995 which resulted not only in immediate deaths but in changes in long-lasting neurological functions. This research will provide valuable new insights into the mechanisms of OP action in the CNS and identify new potential targets for specific pharmacological interventions to ameliorate the effects of OP on the CNS. PUBLIC HEALTH RELEVANCE Organophosphates are inhibitors of the nervous system enzyme acetylcholinesterase inhibitors and are used widely in agriculture as pesticides and also have been used in terrorist attacks against civilian populations. Exposure to organophosphates can cause convulsions and long-term damage to the central nervous system. This research will determine the molecular mechanism for these actions and may identify targets for improved treatment of organophosphate poisoning.